The invention relates to compounds and compositions useful for treating disorders related to Kit.
The enzyme Kit (also called CD117) is a receptor tyrosine kinase (RTK) expressed on a wide variety of cell types. The Kit molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for Kit is stem cell factor (SCF), whose binding to the extracellular domain of Kit induces receptor dimerization and activation of downstream signaling pathways. Kit mutations generally occur in the DNA encoding the juxtumembrane domain (exon 11). They also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations make Kit function independent of activation by SCF, leading to a high cell division rate and possibly genomic instability. Mutant Kit has been implicated in the pathogenesis of several disorders and conditions including systemic mastocytosis, GIST (gastrointestinal stromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma. As such, there is a need for therapeutic agents that inhibit Kit, and especially agents that inhibit mutant Kit.